ABSTRACT Reverse cholesterol transport (RCT) is an important protective mechanism against atherosclerosis, in which plasma high-density lipoprotein cholesterol (HDL-c) interacts with macrophages in arterial wall and shuttles excess of cholesterol back to the liver. In macrophages, the cholesterol efflux activity is controlled by the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Upregulation of ABCA1/ABCG1 in macrophages increases cholesterol efflux activity to HDL particles and decreases atherosclerosis. Kruppel- like factor 14 (KLF14), identified by large genome-wide association studies, is strongly associated with HDL-c level, coronary heart disease (CHD). Our preliminary studies demonstrate that KLF14 increases plasma HDL-c level by modulating hepatic apolipoprotein (apoA-I) production. Intriguingly, we identified that perhexiline, which is clinically used to treat angina and heart failure, is a novel KLF14 activator. Perhexiline-mediated KLF14 activation attenuated atherosclerosis in apoE-deficiency mice. Interestingly, we found that KLF14 regulates cholesterol efflux by upregulation of ABCA1 and ABCG1 in macrophages, which contribute to the availability of cholesterol to apoA-I and HDL. However, perhexiline has sub-optimal pharmaceutical properties such as off-target toxicity, narrow therapeutic index and variable pharmacokinetics. We also demonstrated that synthetic high density lipoprotein (sHDL) nanoparticles could target delivery of drugs to atheroma. These sHDL has been tested in clinical trials at large doses and were found to be safe and have favorable pharmacokinetics. Furthermore, we have developed sHDL-mediated drug delivery platform for atherosclerosis treatment. In this proposal, we will: 1) Determine KLF14 regulates atherosclerotic regression by enhancing cholesterol efflux; 2) Develop sHDL nanoparticles as an efficient atheroma drug delivery system; 3) Determine the ability of sHDL nanoparticles mediated KLF14 activator delivery to promote atherosclerosis regression in vivo. The long-term goal of this project is to understand the function and underlying mechanism of KLF14 in atherosclerosis regression in order to design novel therapeutic strategies for treatment of atherosclerosis.